1. Field of the Invention
The present invention relates to a method for determining the risk of adverse effects of irinotecan and a kit for it.
2. Background Art
Irinotecan (CPT-11) is a synthetic anticancer agent derived from the antitumor alkaloid camptothecin originally isolated from Camptotheca acuminata and is shown to be effective in treating cancers such as lung cancer and metastatic colon carcinoma. While irinotecan demonstrates strong anticarcinoma activity by inhibiting topoisomerase, which promotes DNA replication, it is reported that significant toxicity of irinotecan can induce adverse effects such as leucopenia and diarrhea.
The enzyme UDP-glucuronosyl transferase (UGT) catalyzes glucuronidation reactions of drugs as well as exogenous and endogenous substances such as bilirubin, steroid hormones and bile acid. One of the genes encoding the enzyme is called UGT1A1, which is known to have polymorphisms.
It is reported that polymorphisms in the UGT1A1 gene are related to the occurrence of adverse effects of the anticancer agent irinotecan (CPT-11). More specifically, patients with UGT1A1 polymorphisms resulting in reduced UGT activity are found to have a greater risk of developing serious adverse effects such as leucopenia and severe diarrhea. One of the polymorphisms in the UGT1A1 gene designated as UGT1A1*28A has 7 TA repeats in the TATA box within the promoter region in stead of 6 repeats in the predominant wild type designated as UGT1A1*1. The insertion of these extra two nucleotides (TA) in the variant allele accounts for lowered gene expression of UGT1A1 and results in reduced UGT activity.
Therefore, the detection of UGT1A1 polymorphisms has been expected to serve as an effective means to predict and prevent adverse effects of irinotecan. Conventional methods for polymorphism detection include direct sequencing and fragment analysis. Furthermore, Invader UGT1A1 Molecular Assay for Irinotecan Toxicity (Third Wave Technologies, Inc., USA) is in practical use as a diagnostic product for the detection of UGT1A1 polymorphisms. Unfortunately, a problem with the methods above is that they lack sufficient detection accuracy and they are not cost-effective in detecting the polymorphisms.